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Abstract

The herpes simplex virus type I (HSV-1) is a major human pathogen that infects the majority of the world's population. The life cycle of HSV-1 is controlled by interactions with its hosts. Understanding virus-host interactions will be necessary for developing new therapeutic and preventive strategies against HSV-1, especially in immuno-compromised patients and neonates. An interesting aspect of HSV-1 is how it switches from a productive (lytic) replication cycle to a lifelong latent infection in the sensory neurons; the molecular events involved in this switch are not clearly understood. Consequently, the major goal of this thesis is to examine the role and interactions of viral and cellular proteins in determining the outcome of viral infection. In this thesis, I studied two viral regulatory immediate early proteins (IE), namely infected cell protein 0 (ICP0) and infected cell protein 22 (ICP22). Both proteins are required for efficient viral replication in vivo. Specifically, I characterized in cell culture and in mice how ICP0's functions are regulated via phosphorylation, and I distinguished the functions between ICP22 versus its N-terminally truncated form, US1.5. In the latter experiments, we also identified a novel role for ICP22 in counteracting the type I interferon (IFN) response. Furthermore, I characterized the viral mutant, KOS-NA that contains novel mutation/s within the UL39 gene, which encodes for the large subunit of ribonucleotide reducatese enzyme (ICP6). These mutations in KOS-NA resulted in ICP6 amino acid substitutions that reduced its protein levels, and attenuated viral pathogenesis in vivo, making KOS-NA a potential therapeutic vector in treating HSV-1 diseases. Lastly, I discovered a new relation between the cellular kinase CDK-5, its activating partner p35, and HSV-1 acute infection of neurons. Overall, the data presented in this thesis indicates that multiple viral encoded factors, phosphorylation, cellular factors, and their interactions with one another affect the HSV-1 life cycle.